We had proposed a hypothesis based on precedents in other systems of an intercellular interaction crucial to development between single membrane spanning and seven membrane spanning integral proteins, that one or more forms of the Beta-amyloid precursor protein (Beta-APP) and Presenilin 1 or 2 (PS-1 or 2) may normally be components of an intercellular juxtacrine signaling system (1). We have shown that B-APP and PS-1 and 2 are expressible at the cell surface, that Beta-APP and the presenilins interact intercellularly, that this interaction results in signaling and finally, the most critical test of our hypothesis: that AB is produced as a result of the transcellular binding of Beta-APP with PS-1 or PS-2. In this application we are extending our original hypothesis to propose that intercellular binding of Beta-APP and PS is also required for the cleavage of Beta-APP at the alpha-site. PS-1 appears to regulate not only distinct gamma-secretase activities, but inducible alpha-secretase activity as well (2). No detailed mechanisms have so far been described as to how this might happen. We propose that after cell-cell interaction of Beta-APP with PS-1 or PS-2, either ABeta may be produced via an endocytic pathway, or alternatively, a cell-surface mechanism operates and Beta-APP is cleaved by alpha-secretase, precluding the formation of ABeta. The alpha-cleaved ectodomain of Beta-APP is then shed, possibly triggering a cell-cell de-adhesion, as has been described for the ephrins (3). Therefore, this model proposes that for alpha-cleavage to occur, Beta-APP must first interact intercellularly with PS-1 or PS-2. Our specific aims are: 1. To investigate whether or-cleavage of Beta-APP and ectodomain shedding requires the prior specific cell-cell interaction mediated by the binding of Beta-APP with either PS-1 or PS-2 and to investigate the quantitative relationship of soluble Beta-APP production to ABeta production. 2. To investigate events at regions of cell-cell contact following the intercellular binding of Beta-APP with PS for the activation of alpha-secretase proteolysis of Beta-APP and the possible detachment of the contacting cells. 3. To investigate whether the biochemical signals that are induced by Beta-APP:PS intercellular binding are required for the alpha cleavage of Beta-APP.